The interleukin-2 receptor (IL-2R) is a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to the IL-2 cytokine. The IL-2 receptor is made up of 3 subunits—IL-2Rα, IL-2Rβ, and IL-2Rγ, with each of IL-2Rα and IL-2Rβ having binding affinity for IL-2 while IL-2Rγ alone has no appreciable affinity. Thèze et al. (1994) Immunol. Today 17(10):481-486. Further, the IL-2Rαβ heterodimer has a faster association rate and a slower dissociation rate when binding IL-2 versus either chain alone. Liparoto et al. J. Mol. Recognit. 12(5):316-321.
CD4+ regulatory T-cells, which are responsible for suppressing the immune response, preferentially express the IL-2Rαβ form of the IL-2R. Thus, administration of compounds that are agonists for IL-2Rαβ can be expected to suppress the immune response.
CD8+ memory T-cells, which are responsible for enhancing the immune response, preferentially express the IL-2Rβ form of the IL-2R. Thus, administration of compounds that are agonists for IL-2Rβ can be expected to enhance the immune response (by, e.g., increasing the proliferation of CD8+ memory T-cells).
Thus, administration of IL-2Rβ-selective agonists would be beneficial to patients suffering from certain cancers as doing so is expected to reduce the immune-suppressing effects of regulatory T-cells while increasing CD8+ memory T-cells, thereby recruiting the patient's own immune system to eliminate cancer cells. Optimally, such an IL-2Rβ-selective agonist would also exhibit relatively long exposure following administration, thereby further improving the patient's response to the treatment.
Recruiting the immune system of the cancer patient in the treatment of cancer via administration of IL-2β-selective agonists—which is directly immunoactivating—can be further enhanced through the administration of antagonists of immunosuppressive pathways (e.g., antagonists of CTLA-4 and PD-1).
Thus, the present invention seeks to address (among other things) the continuing need to provide more effective treatments of cancers by, for example, administering to a patient suffering from cancer an IL-2Bβ-selective agonist in combination with a pharmacological-based antagonist of a immunosuppressive pathway.
This and other needs in the art are addressed by the present invention.